PTEN and AR are highly involved in the prostate cancer progression. The linkage between these two antagonistic factors remains unclear. PTEN has been identified as a tumor suppressor containing a dual-specificity protein tyrosine phosphatase and lipid phosphatase domain. PTEN may use its lipid phosphatase activity to negatively regulate cell growth through inhibition of general survival signaling PI3IKIAkt pathway. Several reports have also suggested the existence of PI3K/Akt-independent pathways in PTEN-mediated signaling. Androgen serves as a mitogen for AR-positive prostate cancer cell growth. AR can be activated by some kinase or growth factors in a ligand-independent manner. Invasion inhibition and growth arrest induced by PTEN may require its protein phosphatase activity in some cell lines, but its protein targets still remain largely unknown. AR is a phosphoprotein whose activity is highly regulated by alteration of phosphorylation levels. Our preliminary data found that PTEN could interact with AR in vitro and in viva and suppress AR transactivation, suggesting the existence of a new PTEN-signaling pathway in LNCaP cells. We hypothesize that in addition to the classic PTEN-PI3K-Akt pathway PTEN can also suppress AR by direct interaction with AR via either destabilization of AR protein, slowing down AR nuclear translocation, or changing AR phosphorylation status. The consequence of these events may then result in the suppression of AR-mediated transactivation and cell proliferation. Three Aims will be proposed to test this hypothesis: Aim 1: To dissect the mechanisms of how PTEN suppresses AR transactivation. (1A: by decreasing the AR expression via destabilization of AR protein, 1 B: by a slow-down of the AR nuclear translocation, or 1C: by AR dephosphorylation). Aim 2: To find the minimum interaction domain or mutated PTEN that will interrupt the PTEN suppression of AR function. Aim 3: To determine the growth arrest and cell apoptosis induced by PTEN through the inhibition of AR-mediated pathway. The success of this proposal may provide a new molecular mechanism that may link the tumor growth suppression in AR-positive prostate cancer and may also increase therapeutic approach for prostate cancer patients in the future.